Intra-arterial thrombolytic therapy for the management of acute limb ischemia

INTRODUCTION — Acute limb ischemia (ALI) is a serious limb-threatening condition that can be due to embolism or to thrombosis of an underlying vascular pathology or at the site of a prior revascularization. ALI can progress to a life-threatening situation if not managed efficiently and effectively.

Intra-arterial thrombolytic therapy, which can be administered through a catheter with or without adjunctive mechanical methods, is among several options (eg, open thromboembolectomy, open surgical bypass) available for the treatment of ALI.

The indications for thrombolytic therapy for the treatment of ALI and its efficacy, conduct, and monitoring are reviewed.

The clinical features of ALI, general management principles, and specific etiologies are discussed separately. (See "Clinical features and diagnosis of acute lower extremity ischemia" and "Overview of upper extremity ischemia".)

INTRA-ARTERIAL THROMBOLYSIS — Intra-arterial thrombolysis involves the administration of agents directly into an artery to break down thrombus. While many agents are available, those used for intra-arterial thrombolysis are classified as plasminogen activators. Plasminogen activators achieve thrombolysis by either directly or indirectly activating plasminogen to its active form, plasmin, which then degrades the fibrin blood clot [1].

Thrombolytic agents — Several thrombolytic agents are available, including the first-generation plasminogen activators, streptokinase and urokinase, second-generation plasminogen activators, recombinant tissue plasminogen activator (rTPA; alteplase), and third-generation plasminogen activators (reteplase [r-PA], among many others). For intra-arterial thrombolysis, the most used are rTPA or urokinase rather than streptokinase [1-3]. Newer, third-generation activators provide more targeted therapy with longer half-life, improved safety profile, and better fibrin specificity. While these properties provide benefits particularly for systemic administration, they provide minimal improvement in catheter-directed modalities that are outweighed by the significant increase in costs [1]. Thus, the three most-used agents remain rTPA, urokinase, and streptokinase.

●Tissue plasminogen activator – TPA is derived from the vascular endothelium and is produced artificially using DNA technology as rTPA. The mechanism of action of rTPA is the direct activation of plasminogen. Infused intravenously, rTPA remains relatively inactive within the circulation. However, when connected with the fibrinoid of the thrombus, it is activated, causing the transformation of plasminogen into plasmin with subsequent degradation of the thrombus' fibrinoid. Its half-life is four to seven minutes [4].

●Streptokinase/urokinase – Streptokinase and urokinase plasminogen activators are first-generation plasminogen activators with a similar mechanism to rTPA but with lower fibrin specificity and a theoretically higher risk of hemorrhagic complications. The half-life of streptokinase is 18 minutes, while the half-life for urokinase varies from 6 to 18 minutes [1].

The benefits of one agent as compared with another are multifactorial and generally depend on efficiency of fibrin degradation, safety profile, and cost. Head-to-head in vitro studies have shown that streptokinase has the slowest rate of thrombolysis, urokinase is intermediate, and rTPA is the most efficient [5]. In randomized trials, rTPA has demonstrated improved patency compared with streptokinase but not urokinase [3]. Despite the theoretical improved safety profile of rTPA due to its superior fibrin specificity, this has not been clearly demonstrated when compared directly with the other agents in a controlled setting. Lastly, the increased cost of rTPA as compared with urokinase and streptokinase confounds the determination of which agent is the most cost-effective; however, most evidence demonstrates that urokinase is likely the overall most cost-effective agent [5]. Of note, urokinase is not available in the United States.

Agent selection — The effectiveness and associated bleeding complications vary somewhat for the available thrombolytic agents and are also dose dependent. For thrombolysis in appropriately selected patients, we suggest using tPA or urokinase, rather than streptokinase, for the reasons given above. However, urokinase is no longer available for use in the US. Recommended dosing is discussed below. (See 'Thrombolytic agents' above and 'Thrombolytic dosing' below.)

In addition to the landmark trials discussed above (see 'Surgery versus thrombolysis' below), a Cochrane review evaluated five trials [6-10] to determine the best approach to thrombolytic therapy [11,12]. Studies comparing the three commonly used agents (rTPA, streptokinase, and urokinase) were available. Intra-arterial rTPA was superior to intra-arterial streptokinase, but the outcomes for rTPA versus urokinase were less clear; similar outcomes were noted with regards to vessel patency, limb salvage, bleeding complications, and death. Initial lysis was more rapid for rTPA compared with urokinase. Lastly, while the use of higher doses for rTPA and urokinase led to more rapid lysis, there was no effect on longer-term outcomes, and bleeding complications were increased.

The only head-to-head comparison of thrombolytic agents was a controlled, in vitro study comparing rTPA, urokinase, and streptokinase [5]. The results of this study confirmed those of the Cochrane review in that rTPA was the most efficient in rate of thrombolysis, urokinase was intermediate, and streptokinase was the slowest. The study further reviewed the cost of each drug, and given that the cost of rTPA is significantly higher, determined that urokinase was likely the most cost-effective of the three.

WHEN TO CONSIDER INTRA-ARTERIAL THROMBOLYSIS — The management of acute limb ischemia (ALI) depends on the etiology of obstruction, lesion location and length, duration and severity of symptoms, general condition, comorbidities of the patient, and institutional resources. For many patients, intra-arterial thrombolysis with or without mechanical thromboembolectomy may be the preferred initial approach, provided the limb is not immediately threatened or unsalvageable (table 1). (See 'Specific vascular conditions' below.)

Surgery versus thrombolysis — Several landmark trials completed in the 1990s compared the use of thrombolytics to surgical thrombectomy and provide the basis for selecting patients for treatment [13,14].

●The first was the Rochester series, which randomly assigned 114 patients with Rutherford IIB ischemia and acute symptom onset (<7 days) to intra-arterial catheter-directed urokinase therapy or surgical revascularization. Thrombolytic therapy successfully resolved occluding thrombus in 40 patients (70 percent). Overall, one-year limb salvage rates were similar at 82 percent for both groups. However, one-year survival was significantly improved for the urokinase group (84 versus 58 percent), attributed to lower incidence of cardiopulmonary complications (16 versus 49 percent).

●The Surgery for thrombolysis for the ischemic lower extremity (STILE) trial compared open revascularization versus catheter-directed urokinase or recombinant tissue plasminogen activator for non-embolic lower extremity native artery occlusions with <6 months of worsening ischemia [13]. Of note, the trial was stopped early due to increased rates of complications in the thrombolysis group, but several key findings were noted.

•Patients who presented with <14 days of symptoms who underwent catheter-directed therapy (CDT) had lower amputation rates at six months and shorter length of hospital stay compared with open revascularization or those with treated >14 days after symptom onset with thrombolysis.

•A subanalysis also showed that pretreatment with CDT reduced the need for open revascularization in femoropopliteal and iliofemoral arterial disease. However, those who did undergo open revascularization had less recurrent ischemia or fewer major amputations at one year.

•Factors associated with worse outcomes after CDT included femoropopliteal occlusion, diabetes, and chronic ischemia.

●The Thrombolysis or Peripheral Arterial Surgery (TOPAS) trial was a multicenter trial that randomly assigned patients with ALI (<14 days onset) to catheter-directed urokinase or open surgery. The primary endpoint was amputation-free survival (AFS) [14]. About half of patients presented with acute occlusions of lower extremity bypass grafts. Mortality and AFS were similar between the groups; however, the CDT group experienced more major hemorrhagic complications. The investigators concluded that CDT had similar one-year outcomes but reduced the complexity of any subsequent surgical intervention. This was particularly the case for long occlusions (length ≥30 cm) in which those treated with thrombolysis fared better than those treated with surgery.

Criteria for treatment — Based on the combined findings from available trials, we recommend catheter-directed thrombolysis (with or without mechanical thromboembolectomy) as first-line treatment for acute limb ischemia provided all of the following conditions can be satisfied:

●Symptoms of acute limb-threatening ischemia (table 1) are present for <14 days in the setting of a thrombosed infrapopliteal artery or thrombosed peripheral arterial bypass graft. The use of CDT in more proximal vessels can be considered, but the data are less clear in this setting compared with open thrombectomy/embolectomy or mechanical thrombectomy.

●There are no absolute contraindications to thrombolysis. (See 'Contraindications' below.)

●The predicted time to re-establish antegrade flow is short enough to preserve limb viability.

Patient assessment should focus on timing of symptom onset since CDT is most effective in the first 14 days of symptom onset. For patients with peripheral artery disease (PAD) or aneurysmal disease, in addition to symptom onset, the following clinical scenarios are also generally accepted as indications for CDT:

●Occluded stent or graft presenting within 14 days of symptoms onset

●Comorbidities that preclude use of a general anesthetic

●Fragmented thrombus involving several arterial branches or segments

●Distal small artery obstruction in the setting of a popliteal artery aneurysm

Specific vascular conditions — Various vascular conditions that may indicate thrombolytic therapy (with or without mechanical thromboembolectomy) include the following, which are discussed in more detail in the linked topics.

●Acute embolism – Acute embolism to the upper or lower extremity. Most embolic occlusions involve proximal extremity arteries (eg, femoral, brachial), which can often be managed efficiently by embolectomy; however, more distal embolization can occur. (See "Embolism to the upper extremities" and "Embolism to the lower extremities".)

●Acute thrombosis – Acute thrombosis of underlying pathology.

•Atherosclerosis – Chronic lower extremity atherosclerotic lesion (acute-on-chronic occlusion) secondary to an in situ thrombosis (ie, plaque rupture). (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Threatened limb'.)

•Thoracic outlet syndrome – Thrombosis associated with arterial thoracic outlet syndrome presenting as acute limb ischemia often benefits from thrombolytic therapy prior to surgical decompression. Thrombosis is often associated with a post-stenotic aneurysm that forms in the subclavian artery. (See "Overview of thoracic outlet syndromes", section on 'Managing ischemia'.)

•Popliteal artery aneurysm – Catheter-directed thrombolysis is often used in the management of thrombosed popliteal artery aneurysm to improve the patency of tibial runoff to the foot prior to definitive treatment of the aneurysm with either stent-grafting or open surgical bypass and ligation of the aneurysm. (See "Popliteal artery aneurysm".)

•Nonatheromatous disease – Popliteal artery entrapment syndrome and popliteal adventitial cystic disease can present with acute limb ischemia from popliteal artery thrombosis. (See "Nonatheromatous popliteal artery diseases causing claudication or limb-threatening ischemia".)

●Thrombosis of revascularization – Thrombosis at the site of prior revascularization (eg, stent thrombosis, bypass graft). (See "Endovascular techniques for lower extremity revascularization", section on 'Thrombosis/embolism' and "Lower extremity surgical bypass techniques", section on 'Complications' and "Surgical and endovascular techniques for aortic arch branch and upper extremity revascularization" and "Access-related complications of percutaneous access for diagnostic or interventional procedures", section on 'Thromboembolism'.)

CONTRAINDICATIONS — Contraindications to catheter-directed thrombolysis (CDT) include conditions that preclude the use of the thrombolytic agent due to the risk for bleeding and circumstances under which therapy is not likely to be effective.

Increased risk for bleeding — In conjunction with other resources, we use on the Working Party on Thrombolysis in the Management of Limb Ischemia (table 2), which divided contraindications into absolute, major, and minor based on the risk of bleeding. Older age, once considered an increased risk of intracranial hemorrhage, was not listed as a relative contraindication due to other confounders explaining the increased risk [15].

Treatment not likely to be effective — Scenarios when CDT is considered not to be efficacious include:

●Chronic occlusive disease secondary to atherosclerotic disease. CDT can be considered for patients with acute-on-chronic ischemia depending on the anatomy and distribution of acute thrombus versus chronic disease [16].

●Thrombosis of a surgical bypass or graft placed <14 days prior.

●Acute embolic occlusion of a suprapopliteal vessel that has distal reconstitution of flow where open revascularization via balloon embolectomy, open surgical bypass, or endovascular mechanical thromboembolectomy may be more expeditious in removing the occlusion and restoring perfusion.

Outcomes for thrombolysis are similar to open surgery even for patients with advanced acute limb ischemia (Rutherford IIB) [17], but each patient must be assessed for rapid clinical deterioration requiring more urgent treatment. In patients with advanced ischemia and motor deficits, adjuvant measures such as mechanical thromboembolectomy should be considered to expedite reperfusion.

PREPROCEDURE EVALUATION AND PREPARATION — A thorough history and physical, including any history of arrhythmia, endocarditis, prior embolic events, or hypercoagulable disorders, should be elucidated. A thorough pulse exam should be performed.

Vascular imaging — In cases of arterial embolization, evaluation for the source of embolization should include an echocardiogram and computed tomographic angiogram of the chest, abdomen, and pelvis with runoff. (See "Embolism to the lower extremities", section on 'Etiology'.)

Arterial duplex ultrasound can also be used to determine the extent of the arterial occlusion.

Baseline laboratory studies — It is general practice to obtain a baseline fibrinogen and activated partial thromboplastin time prior to catheter-directed thrombolysis infusion. Serial hemoglobin levels and platelet counts are often used as well to monitor for signs of acute blood loss. For patients with multiple prior thromboembolic events, evaluation for an underlying hypercoagulable state should be considered.

CATHETER DEVICES — Available devices for catheter-directed therapy (CDT) include standard infusion catheter systems (eg, UniFuse) and ultrasound-enhanced thrombolysis catheters (eg, Ekosonic Endovascular system [EKOS]). CDT allows for enzymatic clot dissolution, which has been shown to be particularly effective in the distal small vessel or infrapopliteal vascular beds, providing a more complete revascularization as compared with isolated balloon embolectomy in this scenario [18].

Pharmacomechanical thrombolysis involves the additional use of a mechanical force to assist in breaking up the clot. In general, this is initiated by lacing the thrombus with the thrombolytic agent of choice. The mechanical aspect then follows and takes on many forms, including pure aspiration or aspiration along with other assisted measures [19,20]. The presumed benefit of pharmacomechanical thrombolysis as compared with standard CDT is to reduce the overall thrombolysis time as well as overall dose of the lytic agent.

Mechanical devices include those that provide rheolytic thrombectomy (eg, Angiojet) and aspiration thrombectomy (eg, Penumbra), which have shown promising results for catheter-directed revascularization with the use of combined mechanical suction thrombectomy and lytic therapy; however, treatment of smaller distal vessels with these techniques poses several notable risks, including vessel spasm, dissection, rupture, and plaque disruption with distal embolization [21-23]. Thus, some advocate using a distal filter when performing pharmacomechanical thrombolysis to prevent distal embolization, while others would manage such events with either aspiration thrombectomy or prolonged intra-arterial thrombolytic infusion.

INTRA-ARTERIAL THROMBOLYSIS TECHNIQUE — Prior to initiating thrombolysis, patients should be screened for contraindications to thrombolytic therapy (table 2) [13]. (See 'Contraindications' above.)

Thrombolytic therapy can be initiated in a hybrid operating room suite, a standard operating room with portable C-arm capabilities, or an interventional suite. Whenever thrombolysis is performed, it is important to have an operating room available in the event that ischemia progresses during thrombolysis, the treatment fails, or bleeding occurs that requires operative intervention.

Our stepwise approach to intra-arterial extremity thrombolysis is as follows:

●Obtain vascular access (see 'Access the artery' below)

●Initial arteriography (see 'Initial arteriography' below)

●Cross the thrombosis (see 'Cross the thrombosis' below)

●Position the catheter (see 'Position the catheter' below)

●Administer the lytic agent (see 'Administer lytic agent' below)

●Monitor for resolution (see 'Monitor' below)

●Repeat arteriography (see 'Repeat arteriography' below)

Access the artery — Generally, vascular access is obtained via ultrasound-guided percutaneous access to the common femoral artery. Avoiding multiple access attempts or access vessel trauma is always important but particularly so when a thrombolytic agent will be used to avoid access site complications and the reason why using ultrasound for access guidance is essential. Either retrograde or antegrade access can be used depending on operator comfort and proximity of the thrombus to the ipsilateral common femoral artery. In the setting of contralateral iliac artery occlusion or in a raised bifurcation due to prior iliac stenting, brachial artery access can be used for an antegrade approach to the lesion.

Initial arteriography — A diagnostic angiogram is then performed, and the access sheath is exchanged for a 6 Fr sheath for most catheter-directed thrombolytics (CDT) systems. (See 'Catheter devices' above.)

Cross the thrombosis — Attempts are then made to cross the occlusion with a wire followed by the infusion catheter. The ability to easily cross the thrombus is a positive prognostic factor for successful thrombolysis. If unable to cross the lesion, then the catheter is positioned just proximal to the occlusion. It is important that the catheter remains intraluminal in this setting; subintimal passage should be avoided.

Position the catheter — The catheter is positioned either into the thrombus if the occlusion can be crossed or just proximal to the occlusion if not. The thrombolytic agent is generally infused though a multi-side-hole infusion catheter that is placed over the wire within the extent of the thrombus. The multi-side-hole catheter must be long enough to encompass the length of the involved segment. For small vessel thrombosis (ie, tibial artery), consideration should be given to placing the lytic catheter proximal to the lesion, because the catheter itself can sometimes be occlusive.

Administer lytic agent

Thrombolytic dosing — Once the catheter has been positioned, a bolus of the thrombolytic agent is generally administered through the catheter, and a continuous electronic infusion is initiated. We bolus 4 to 10 mg of recombinant tissue plasminogen activator (rTPA) at the time of catheter placement. The Society of Interventional Radiology recommends weight-based doses of rTPA, 0.02 to 0.1 mg/kg/hr; however, most clinicians use standard doses of 0.5 to 1 mg/hr for low-dose infusions, with the overall maximum dose limit of 40 mg [24]. High-dose infusions of >1 mg/hr have been used and typically lead to a slightly higher bleeding risk with comparable outcomes and the benefit of shorter infusion times (21.9 hours for high-dose versus 32.7 hours for low-dose infusions) [2]. After securing the catheters, the patient is transferred to an intensive care unit for monitoring. (See 'Monitor' below.)

Concomitant heparin administration — The concomitant use of a continuous unfractionated heparin (UFH) infusion remains controversial [25-29]. Several studies show no advantage or disadvantage to its use, while others, including the TOPAS trial [14], demonstrated increased bleeding risk with the use of UFH.

Many centers administer low-dose UFH infusions via the access sheath to prevent sheath thrombosis; however, no data for this practice exist [2]. Our practice is to administer unfractionated heparin through the side arm of the sheath (500 units/hour) to limit thrombosis of the sheath.

Monitor — After initiation of CDT, we admit the patient to the intensive care unit to monitor the limb for improvement or worsening limb ischemia, bleeding, compartment syndrome, or other complications (eg, acute neurologic changes).

Resolution or progression — We perform lower extremity neurovascular checks every hour. Any signs of clinical deterioration in motor or sensory function, particularly in patients with more advanced ischemia (Rutherford IIA/IIB), warrants a more expedient approach to restoration of arterial perfusion, typically surgical revascularization (eg, embolectomy, bypass grafting).

Rarely, patients can develop compartment syndrome if reperfusion is substantial, warranting a fasciotomy. (See "Lower extremity fasciotomy techniques".)

Complications — The patient is closely monitored for signs of bleeding complications. Fibrinogen and activated partial thromboplastin time (aPTT) values are often monitored every six to eight hours while the catheter is in place to titrate the lytic infusion and to minimize major systemic adverse bleeding events (eg, intracranial hemorrhage) from the ensuing coagulopathy. This practice likely stems from results in the STILE trial that reported a correlation between low levels of fibrinogen and bleeding complications [13]. Later data, including a systematic review, have not demonstrated this correlation, leading many clinicians, particularly those in Europe, to abandon this practice [30-33].

Our practice is to obtain hemoglobin, hematocrit, platelet counts, aPTT, and fibrinogen every six hours to monitor for bleeding risk as well as for the possible development of thrombocytopenia or hypofibrinogenemia. For fibrinogen <150 mg/dL or a drop in fibrinogen greater than one-half of the previous level, we generally reduce the rate of infusion by one-half, and if the fibrinogen falls below 100 mg/dL, we hold the infusion for one hour, and then recheck fibrinogen levels. If fibrinogen levels are low and there is concern for bleeding, fresh frozen plasma or cryoprecipitate can be transfused, but this is rarely needed. There are limited data to support this practice, and this approach is predominantly based on clinical experience managing these patients.

Repeat arteriography — The need for ongoing infusion or an increase in dose, possible repositioning of the catheter, or another course of therapy is determined by repeat arteriography (daily or in response to clinical changes). If initial progress is slow, the infusion can be increased to 1.5 to 2 mg/hour. If needed, the infusion can be continued up to two to three days, provided the extremity is not threatened.

OUTCOMES — Technical success rates, defined as complete or partial lysis of the occlusion, for catheter-directed thrombolytics (CDT) in acute limb ischemia are as high as 80 to 90 percent [29,34,35]. In general, outcomes of thrombolytic therapy are best for native arterial lesions [36,37]. However, in one review, success rates were higher for endoprosthesis/prosthetic bypasses (approximately 90 percent) compared with native vasculature (73 percent) [35]. For acute limb ischemia, amputation-free survival with CDT resembles the technical success rates, with reported rates of 83.6 percent at 30 days [29] and 73 percent at one year [35]. The outcomes for specific etiologies indicating the need for thrombolytic therapy are discussed separately. (See 'Specific vascular conditions' above.)

COMPLICATIONS — Hemorrhage is the most common complication associated with catheter-directed thrombolytics (CDT), occurring in up to 30 percent of cases in some series [29]. Severe bleeding complications of thrombolysis include intracranial hemorrhage, which has high mortality, and major gastrointestinal bleeding, which is potentially life-threatening.

Intracranial hemorrhage is the most feared complication, occurring in 0.4 to 2.3 percent of cases, and is typically fatal [29,38]. Vascular access complications, most often in the form of a groin hematoma, are also common with CDT therapy and can be reduced with the use of ultrasound guidance when obtaining access [39].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute extremity ischemia".)

SUMMARY AND RECOMMENDATIONS

●Acute limb ischemia – Acute limb ischemia (ALI) is a serious limb-threatening condition that can be due to embolism or thrombosis of an underlying vascular pathology. Intra-arterial catheter-directed thrombolysis is one of several treatment options for ALI. (See 'Introduction' above.)

●Thrombolysis – Intra-arterial thrombolysis involves the administration of thrombolytic agent directly into an artery to break down thrombus. Some systems also include mechanical force to break up thrombus (ie, mechanical thromboembolectomy). Thrombolytic agents used for intra-arterial thrombolysis are classified as plasminogen activators. The most used agents are recombinant tissue plasminogen activator (rTPA), urokinase, and streptokinase. Urokinase and rTPA are associated with better outcomes compared with streptokinase. Agent selection also depends on availability and clinical experience. (See 'Thrombolytic agents' above.)

●Indications – A patient with ALI may be a candidate for intra-arterial thrombolysis depending on the severity of limb threat (table 1), etiology of ALI, and other patient factors, and provided there are no absolute contraindications to intra-thrombolysis (table 2). For patients who are candidates, we pursue intra-arterial thrombolytic therapy within 14 days of acute symptom onset, provided the predicted time to re-establish antegrade flow will not jeopardize limb viability. Landmark trials that established the effectiveness of intra-arterial thrombolysis noted reduced success when treatment occurred later than this timeframe. Nevertheless, thrombolysis can be attempted past this time frame in selected patients with a low risk for bleeding. (See 'When to consider intra-arterial thrombolysis' above and 'Contraindications' above.)

●Technique – Intra-arterial thrombolysis is performed in a stepwise fashion that includes accessing the artery, performing initial arteriography, crossing the thrombosis, positioning the catheter, administering the lytic agent as a bolus followed by a continuous infusion, and monitoring for resolution or progression of ischemia, which may indicate the need for repeat arteriography and increased dosing, or more urgent surgical intervention. Specific techniques are described above. (See 'Intra-arterial thrombolysis technique' above.)

•Infusion – Once arterial access is obtained and the thrombus is crossed, our protocol is to bolus 4 to 10 mg rTPA followed by an infusion of 0.5 to 1.0 mg/hr. We also administer 500 units/hour of unfractionated heparin to the side port of the sheath to prevent sheath thrombosis.

•Monitoring – We perform frequent (every hour) lower extremity neurovascular checks and evaluate for clinical signs of bleeding, and monitor the hemoglobin, hematocrit, platelets, partial thromboplastin time and fibrinogen every six hours during rTPA infusion, holding or discontinuing the infusion for signs of bleeding (eg, intracranial, gastrointestinal) or significant reductions in laboratory values (eg, fibrinogen <150 mg/dL) as described above. (See 'Monitor' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Graeme E McFarland, MD, and Victoria J Aucoin, MD, who contributed to earlier versions of this topic review.